This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Skeletal muscle possesses remarkable regeneration potential, which largely is attributable to satellite cells and other muscle stem cells that reside in adult muscle. Satellite cells, therefore, are of great interest for therapeutic applications for muscle injury and degenerative diseases. To develop effective therapeutics based on satellite cell biology, it is critical to identify key signaling factors, pathways, and mechanisms that regulate their proliferation and/or differentiation during muscle repair and regeneration. R-spondins are a novel class of secreted proteins that activate Wnt/beta-catenin pathways. The PI's laboratory has discovered R-spondin2 expression is markedly and selectively increased during muscle regeneration, with close overlapping timing with satellite cell proliferation and myogenic differentiation. This suggests that R-spondin2 may selectively promote proliferation and/or differentiation of skeletal muscle satellite cells via Wnt signaling pathways. Using in vitro primary cell culture and in vivo mouse models, we will 1) determine the roles of R-spondin2 in promoting proliferation and/or myogenic differentiation of satellite cells, and define key R-spondin2 signaling pathways;and 2) determine how gain or loss of R-spondin2 function affects skeletal muscle regeneration in vivo.